The present invention relates to a method for preparing a salt of acetylsalicylic acid and of a basic amino acid, in particular lysine. This method makes it possible in particular to obtain, with a high degree of purity, such a salt having a particularly high stability over time.
Acetylsalicylic acid has been used for many years in the therapeutic field, in particular for its analgesic, anti-inflammatory, antipyretic, anti-rheumatic and platelet aggregation-inhibiting effects. Its solubility in water is however limited, so that it can only be administered in galenical forms containing it in the solid state, and orally.
In order to improve the solubility of acetylsalicylic acid, in particular in water, it has been proposed by the prior art to provide it in the form of a basic amino acid salt. DL-lysine acetylsalicylate thus at the current time constitutes the active ingredient of several medicaments.
A major drawback of DL-lysine acetylsalicylate is its poor stability, in particular because of its hygroscopic nature, so that pharmaceutical formulations which contain it have a limited shelf life. This instability has been explained by a chain of reactions resulting, in the presence of moisture, in the formation of a specific degradation product, salicylic acid, the presence of which in the pharmaceutical formulation is undesirable.
Processes for producing lysine acetylsalicylate aimed at improving the stability of the latter have been proposed by the prior art.
Mention may in particular be made of document US 2002/0091108, which describes a process for producing lysine acetylsalicylate comprising rapid mixing of acetylsalicylic acid and lysine, under conditions of molar excess of lysine, this mixing being followed by cooling of the reaction medium to 0° C. concomitantly with the addition of a large volume of acetone, so as to allow the formation of crystals by stirring of the reaction medium for several hours. However, such a process is lengthy to carry out and it is consequently associated with high production costs. In addition, the degree of purity of the lysine acetylsalicylate that it makes it possible to obtain is insufficient to meet the specifications of the pharmacopeia for use as a medicament active ingredient.
The prior art has alternatively proposed, in particular illustrated by document WO 2011/039432, document FR 2 973 370 or document WO 2011/039432, to prepare DL-lysine acetylsalicylate by mixing acetylsalicylic acid and DL-lysine, under conditions of molar deficiency of DL-lysine. The reaction medium is then diluted in a large volume of acetone, so as to bring about the precipitation of the desired salt. However, it has been noted by the present inventors that the stability of salt of acetylsalicylic acid and lysine thus obtained is insufficient. This process also does not make it possible to obtain this salt with a satisfactory degree of purity.